The epilepsies are a diverse group of disorders characterized by abnormal electrical activity in the CNS, affecting up to 3% of the population. Of this group, approximately 40% are idiopathic in which the underlying cause is most likely a genetic abnormality. The specific abnormality has been identified in only a small minority of cases, most of which are channelopathies involving defects in ion channel function. Even in those cases, the mechanisms by which the defects result in epilepsy are not understood. One class of channelopathies that cause epilepsy are mutations in voltage-gated sodium channels, which cause a number of different syndromes including Generalized Epilepsy with Febrile Seizures Plus (GEFS+). The goal of this research is to determine how abnormal sodium channel function resulting from mutations causing GEFS+ leads to epilepsy. There are three goals. The first aim is to determine which neuronal populations express the GEFS+ mutant sodium channels and to characterize the mutant channels in those cells. This will be accomplished by identifying the specific interneuron cell types that express the R1648H mutant sodium channels and using electrophysiological techniques to analyze dissociated neurons from mice in which specific populations are tagged with fluorescent proteins. The second aim is to determine the mechanism by which altered sodium channel activity resulting from the R1648H mutation leads to greater seizure susceptibility in GEFS+. This will be accomplished by recording from cortical and hippocampal slices from knock-in mice expressing the mutation. We will determine the effects of the mutation on the firing properties of specific classes of neurons, on seizure-like activity in field recordings, and on intrinsic excitability of the excitatory and inhibitory neurons and the quantitative effects of synaptic input using laser scanning photostimulation. The final aim is to determine if a second GEFS+ mutation (D1866Y) also causes decreased firing of inhibitory neurons in the CNS and to determine the role of the b1 subunit in the phenotype of this mutation. This will be accomplished by recording from dissociated cells and slices from knock-in mice expressing the mutation, and examining the effects of the D1866Y mutation in mice lacking the b1 subunit. These studies should enhance our knowledge concerning the physiological and pathological events leading to one specific form of epilepsy.